Higher Probability Of Response Research Articles

Antifungal Drug Plasma Exposures: A Possible Contribution of Vitamin D-Related Gene Variants.

Vitamin D (VD) seems to influence drug clearance and outcome. Antifungal drugs (AFU) are the most used azoles in clinical practice. In the literature, no data are available concerning VD’s impact on AFU therapy. The aim of this study was to analyze if VD pathway-related polymorphisms may influence voriconazole (VRC), itraconazole (ITC), and posaconazole (PSC) drug concentrations in order to identify patients with the highest probability of response and toxicity. Allelic discrimination was performed through real-time PCR, whereas drug concentrations were through liquid chromatography. A total of 636 samples of AFU-treated patients were included in the analysis. Concerning VRC, concentrations higher than the 1000 ng/mL efficacy cut-off value were predicted by Caucasian ethnicity, CYP24A1 3999, and CYP27B1 + 2838 polymorphisms, whereas levels higher than the 5000 ng/mL toxicity value by Caucasian, female sex, e.v. administration, and GC 1296. Considering PSC, concentrations higher than the 700 ng/mL efficacy cut-off value were predicted by VDR Cdx2, CYP27B1 − 1260, and GC 1296. Finally, for ITC, VDR BsmI was the only predictor of drug exposure higher than the 500 ng/mL efficacy cut-off value, whereas female sex, CYP27B1 − 1260, and VDR TaqI remained in the final regression model related to concentrations higher than the 1000 ng/mL toxicity-associated cut-off value. This is the first study reporting the influence of VD pathway-related gene SNPs on AFU exposures, efficacy, and toxicity.

Predictors of objective response to first-line immuno-oncology combination therapies in metastatic renal cell carcinoma: Results from the international metastatic renal cell database consortium (IMDC).

310 Background: Predictors of objective response to first-line (1L) immuno-oncology (IO) combination therapies remain elusive. We sought to characterise clinical variables and their association with investigator assessed best overall response. Methods: Using the IMDC, we retrospectively identified patients treated with 1L ipilimumab nivolumab (IPI-NIVO) or approved IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). Patients were classified, per RECIST v1.1, as responders (complete or partial response (CR or PR)) or non-responders (stable or progressive disease (SD or PD)). Logistic regression was used to adjust for IMDC criteria. Results: Out of 1084 patients, 794 (73%) received IPI-NIVO and 290 (27%) received IOVE (axitinib+pembrolizumab, cabozantinib+nivolumab, axitinib+avelumab, lenvatinib+pembrolizumab). Favourable, intermediate and poor IMDC risk comprised 147 (16%), 517 (55%) and 272 (29%) respectively. Of the 898 patients with evaluable responses, 37 (4%) achieved a best response of CR, 343 (38%) PR, 315 (35%) SD and 203 (23%) PD. Corresponding median overall survival from time of 1L initiation was: not reached, 55.9, 48.1, and 13 months respectively (logrank p < 0.0001). In a multivariable model, lung metastases and cytoreductive nephrectomy (CN) (performed after diagnosis of metastatic disease and before 1L therapy) retained independent association with response, after adjustment for IMDC criteria. Factors not associated with response included (with univariable p values): gender (p = 0.58), age (p = 0.06), sarcomatoid histology (p = 0.99), smoking status (p = 0.39), liver (p = 0.63) and brain (p = 0.12) metastases. As in the VEGF monotherapy era, improved IMDC prognostic risk was associated with response. Results were similar when restricted to the IPI-NIVO cohort. Conclusions: Presence of lung metastases, CN and better IMDC risk group are associated with a higher probability of response to 1L immunotherapy combination regimens. Further work to identify reliable predictors of response to guide treatment selection and patient counselling is warranted.[Table: see text]

Integrating a Prevention Care Path into the Daily Life of Older Adults with Mobility Disability Risk: Introducing a Predictive Response Model to Exercise.

IntroductionExercise and nutrition are the best targets to tackle mobility issues in community-dwelling older adults. As exercise response relies on multiple factors, improving the understanding of their interactions is a necessity to tailor effective preventive strategies. Based on a prevention care path designed for community-dwelling older adults with mobility disability risk, our main goal was to determine the predictive factors of the response to a multimodal intervention, combining structured exercise training and nutritional counselling. Thus, this study aimed to tailor prevention programs for non-responder participants.MethodsWe analyzed the response of participants to a prevention program and built a multivariate predictive model to highlight the profile of the best responders. The model was based on the likelihood of at least 1 point of short physical performance battery (SPPB) score gain. Inclusion criteria were being aged ≥70 years and having completed a multicomponent group-based supervised training consisting of 20 sessions (10 weeks).ResultsA total of 103 participants were included, their mean ± SD age was 81.9 ± 5.7 years. The model demonstrated interactions between baseline SPPB score (OR=0.42; p < 0.001), body mass index (BMI; OR=0.82; p=0.003), and grip strength value (OR=1.15; p=0.008). The highest probability of response was found for participants with low SPPB, normal BMI (21 kg/m2), and high grip strength (27 kg).ConclusionThis study demonstrated that the response to a multimodal intervention in community-dwelling older adults with mobility disability risk was influenced by the baseline SPPB score, BMI, and grip strength value. To increase the proportion of responders, strategies that could be more effective include constituting more homogenous group, and implementing a specific approach for obese sarcopenic older adults and those with low grip strength by increasing the dose of physical activity and monitoring endurance and mobility activities between sessions. Our results provide important consideration for the development of targeted-interventions.

BRCA mutations and gastrointestinal cancers: When to expect the unexpected?

BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer, while their role in gastrointestinal (GI) malignancies such as colorectal cancer (CRC), gastric cancer and oesophageal cancer (OeC) is still not well established. The main objective of this review is to summarise the available evidence on this matter. The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies. Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal, gastric and OeC, albeit with differences among these diseases: In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC. Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations. The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds, where it is expected that a higher probability of response should be seen. A few clinical trials focused on poly (ADP-ribose) polymerase inhibitors use in GI cancers are currently ongoing.

A phase II study of neoadjuvant chemotherapy followed by organ preservation in patients with muscle-invasive bladder cancer

ObjectiveConservative approaches in muscle-invasive bladder cancer (MIBC) have been evolved to avoid aggressive surgery, but are limited to elderly, frail, and patients medically unfit for surgery. Our study aimed to assess the response rate of neoadjuvant chemotherapy (NACT) before radiotherapy (RT) in MIBC patients. MethodsForty patients with urothelial carcinoma of stage T2–T4a, N0, M0 were enrolled between November 2013 and November 2015, and treated with three cycles of NACT with gemcitabine-cisplatin. Post-NACT response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Patients who achieved complete response (CR) and partial response (PR) >50% were treated with radical RT, and those who had PR <50%, stable disease (SD), and progressive disease (PD) underwent radical cystectomy (RC). Survival analysis was done with Kaplan-Meier method and point-to-time events were analyzed with Cox-proportional hazards regression model. ResultsAfter NACT, 35 (87.5%) patients achieved either PR >50% or CR, and were treated with RT. Five (12.5%) patients who had PR <50%, SD, or PD underwent RC. All patients who received radiation showed CR after 6 weeks. Median follow-up was 43 months (range: 10–66 months) and median overall survival (OS) was not reached. Three-year OS, local control, and disease-free survival were 70.1%, 60.9%, 50.6%, respectively, and 50% of patients preserved their functioning bladder. Three-year OS rate was 88.9% in patients who achieved CR to NACT, 73.1% in patients with PR ≥50% and 40% in patients with PR <50%. ConclusionNACT followed by RT provides a high probability of local response with bladder preservation in CR patients. Appropriate use of this treatment regimen in carefully selected patients may omit the need for morbid surgery.

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

BackgroundThe combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance.Patients and methodsThis is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen.ResultsFrom July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS.ConclusionsThe combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity.EudraCT number2012-003505-10.

Predictive Model of Response to Blinatumomab Therapy in Children and Adults with Relapsed/Refractory B-ALL

Background .Blinatumomab is a monoclonal BITe antibody recently introduced for the treatment of relapsed and refractory (r\r) B-ALL. Response rate reaches 65-85% in different subgroups of patients but currently there is no reliable methods to predict response. Using results of the analysis of the efficacy of blinatumomab therapy in heterogenic cohort r/r B-ALL patients, including adults and children, we built a mathematical model to predict response to this antibody. Patients and methods.A total of 128 pts with r\r B-ALL were included in the analysis, 52 children and 76 adults. Median age was 19 years (1-52). Hematological relapse (hr/r) and persistent measurable residual disease - molecular relapse (mr/r) were in 54% and 46% patients, respectively. Significant predictors of response in the multivariate analysis were used in the modeling for assessment of the probability of response to blinatumomab therapy. For validation of adjusted logistic regression parameters a k-fold cross-validation was performed. Confidence intervals for the model efficiency scores were calculated. Results. The response rate to blinatumomab in the study cohort was 75%. In the univariate and multivariate analysis the following parameters had the highest significance for response: patient age (OR=12,06, 95% CI 3,6-40, p&amp;lt;0,001), short mean time (less 18 months) to next line of treatment (OR=0,17, 95% CI 0,05-0,5, p=0,002) and bone marrow blast percentage (OR=0,06, 95% CI 0,01-0,2, p&amp;lt;0,001). The resulting ROC-curve for the regression model is given in figure 1A. The sensitivity/specificity trade-off depending on a decision threshold level in given in figure 1B. For the final classification model for predicting response to blinatumomab therapy in pts r/r B-ALL decision-making threshold was adjusted for obtaining maximum specificity- 0,85, sensitivity -0,5 (i.e. select the patients who will very likely respond). Using this model, the following guiding maps were calculated (figure 1C). The following confusion matrix was obtained when applying the resulting model to the full database: the specificity was 90% (ratio 30/3) and sensitivity was 50% (ratio 44/45). From the confusion matrix the following confidential internals for sensitivity and specificity were estimated: sensitivity - point estimation= 0,51 (95% CI 0,4-0,61), specificity - point estimation= 0.91 (95% CI 0,76-0,98). Conclusions.The possibility of response to blinatumomab therapy depends on patient's age, the bone marrow blast percentage and early relapse. The model predicts the response to blinatumomab therapy in patients with r/r B-ALL with high specificity and reasonable sensitivity and will be able to optimize the use of this very expensive therapy. Based on the model high probability of response in case of short time to next line of therapy is observed only for adult patients with low-to-moderate blast count, while in patients with long time to next line of therapy broader patient population has a high probability of response, including young children and patients with high blast count. Verification of this model in a larger multicenter study is required to confirm this hypothesis. Figure Disclosures No relevant conflicts of interest to declare.

Next generation flow cytometry for MRD detection in patients with AL amyloidosis

The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicated; residual light chain production may still exist while clonal relapse may occur. We used sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response. MRD evaluation was feasible in 51 of 52 (98%) tested patients and at a median sensitivity of 2.3 × 10−6 MRD was undetectable in 23 (45%). An organ response occurred in 86% of MRDneg vs 77% in MRDpos; renal response in 15/17(88%) of MRDneg vs in 14/16(87.5%) of MRDpos and cardiac response in 10/10(100%) of MRDneg vs 11/15(73%) of MRDpos patients. After a median follow-up of 24 months post MRD testing, no MRDneg patient had a haematologic relapse vs 6/28(21%) MRDpos (p = .029). Pooling haematologic and organ progressions, 9 (32%) MRDpos patients had disease progression vs only 1 (4%) MRDneg patient (p = .026). In conclusion, MRD detection using NGF has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haematologic relapse.

Early Intervention With Vedolizumab on Longer Term Surgery Rates in Crohn's Disease: Post Hoc Analysis of the GEMINI Phase 3 and Long-term Safety Programs.

BackgroundCrohn’s disease [CD] is a chronic inflammatory bowel disease that, with progression, may require surgical intervention.AimTo determine whether vedolizumab treatment of CD earlier in the disease course [≤2 or ≤5 years of disease duration] influences risk of CD-related surgery after accounting for probability of response.MethodsPost hoc analyses of data from CD patients treated with vedolizumab in the GEMINI 2, GEMINI 3, and GEMINI LTS trials [N = 1253] evaluated CD-related surgery [bowel resection or colectomy] with stratification by probability of response to vedolizumab [low/intermediate or high]. Analyses used a previously validated clinical decision support tool and both logistic regression and Cox proportional hazard analyses.ResultsIn total, 113 [9.0%] vedolizumab-treated patients required CD-related surgery. Surgical rates were 6.1% and 9.8% for the high and low/intermediate probability of response groups, respectively. Risk of surgery was lower for patients with a high probability of response versus those with a low/intermediate probability of response (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.29 to 0.85). For patients with a low/intermediate probability of vedolizumab response, there was a consistent trend for association between earlier treatment [≤2 or ≤5 years since diagnosis] and a lower risk of surgery relative to later treatment (≤2 years versus >2 years: odds ratio [OR] 0.77, 95% CI 0.38 to 1.58; ≤5 years versus >5 years: OR 0.61, 95% CI 0.37 to 1.00].ConclusionsEarlier intervention with vedolizumab may be associated with lower rates of surgery. Use of the clinical decision support tool may help identify patients most likely to benefit from earlier intervention with vedolizumab.

Omitting surgery for early breast cancer showing clinical complete response to primary systemic therapy

Breast cancer is highly sensitive to systemic therapy. High probability of pathological complete response suggests a clinical question that omitting surgery is an effective alternative to surgery in breast cancer showing clinical complete response to primary systemic therapy. However, the validity of omitting surgery for early breast cancer after primary systemic therapy has not been sufficiently established; thus, even if pathological complete response is expected in patients showing clinical complete response, excision of the primary tumor site remains the standard treatment of breast cancer. Inappropriate omitting surgery increases the incidence of local recurrence, which can be the risk of a subsequent distant metastasis and reduced overall survival. To achieve acceptable local control rate, omitting surgery should be investigated in patients with early breast cancer where a high percentage of pathological complete response, a high concordance rate between clinical complete response and pathological complete response and an acceptable local control rate are expected. This review presents concept and ongoing clinical trials for omitting surgery for patients with breast cancer showing clinical complete response to primary systemic therapy.

Development and Validation of Clinical Scoring Tool to Predict Outcomes of Treatment With Vedolizumab in Patients With Ulcerative Colitis

BACKGROUND & AIMS:We created and validated a clinical decision support tool (CDST) to predict outcomes of vedolizumab therapy for ulcerative colitis (UC).METHODS:We performed logistic regression analyses of data from the GEMINI 1 trial, from 620 patients with UC who received vedolizumab induction and maintenance therapy (derivation cohort), to identify factors associated with corticosteroid-free remission (full Mayo score of 2 or less, no subscore above 1). We used these factors to develop a model to predict outcomes of treatment, which we called the vedolizumab CDST. We evaluated the correlation between exposure and efficacy. We validated the CDST in using data from 199 patients treated with vedolizumab in routine practice in the United States from May 2014 through December 2017.RESULTS:Absence of exposure to a tumor necrosis factor (TNF) antagonist (+3 points), disease duration of 2 y or more (+3 points), baseline endoscopic activity (moderate vs severe) (+2 points), and baseline albumin concentration (+0.65 points per 1 g/L) were independently associated with corticosteroid-free remission during vedolizumab therapy. Patients in the derivation and validation cohorts were assigned to groups of low (CDST score, 26 points or less), intermediate (CDST score, 27–32 points), or high (CDST score, 33 points or more) probability of vedolizumab response. We observed a statistically significant linear relationship between probability group and efficacy (area under the receiver operating characteristic curve, 0.65), as well as drug exposure (P < .001) in the derivation cohort. In the validation cohort, a cutoff value of 26 points identified patients who did not respond to vedolizumab with high sensitivity (93%); only the low and intermediate probability groups benefited from reducing intervals of vedolizumab administration due to lack of response (P = .02). The vedolizumab CDST did not identify patients with corticosteroid-free remission during TNF antagonist therapy.CONCLUSIONS:We used data from a trial of patients with UC to develop a scoring system, called the CDST, which identified patients most likely to enter corticosteroid-free remission during vedolizumab therapy, but not anti-TNF therapy. We validated the vedolizumab CDST in a separate cohort of patients in clinical practice. The CDST identified patients most likely to benefited from reducing intervals of vedolizumab administration due to lack of initial response. ClinicalTrials.gov no: NCT00783718

Combination of host immune metabolic biomarkers for the PD-1 blockade cancer immunotherapy.

BACKGROUNDCurrent clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values.METHODSWe investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab (n = 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated.RESULTSThe 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC = 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8+PD-1hi and CD4+ T cells demonstrated even higher prediction value (AUC = 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set (n = 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC = 0.92).CONCLUSIONCombination of biomarkers reflecting host immune activity is quite valuable for responder prediction.FUNDINGAMED under grant numbers 18cm0106302h0003, 18gm0710012h0105, and 18lk1403006h0002; the Tang Prize Foundation; and JSPS KAKENHI grant numbers JP16H06149, 17K19593, and 19K17673.

P802 Probability of vedolizumab response as defined by clinical decision support tool is associated with lower healthcare utilisation in patients with Crohn’s disease

Abstract Background A clinical decision support tool (CDST) has been developed and validated for predicting treatment effectiveness of vedolizumab (VDZ) in Crohn’s disease (CD). We evaluated this tool’s ability to predict healthcare resource utilisation using real-world data. Methods CD patients treated with VDZ were identified using real-world data from the Optum (n = 358) and Truven MarketScan (n = 1445) databases. The full CDST with 3 clinical variables (prior bowel surgery, prior fistulising disease, prior TNF-antagonist exposure) and 2 lab values (albumin and CRP) was applied to the Optum dataset with available lab data, and patients were stratified into low (n = 27), intermediate (n = 152), or high (n = 179) probability of response groups. A modified weighting of the 3 clinical variables was created for application in Truven MarketScan due to the lack of availability of lab data. To assess the coherence with the full 5-variable CDST, the modified 3-variable CDST was used to stratify Optum patients into low (n = 137) or high (n = 221) probability of response, and then subsequently validated in the Truven MarketScan dataset (low, n = 510; high n = 935; response probability groups). Rates of hospitalisation, surgery, emergency department (ED) visits and annualised per patient costs were compared across response probability groups. Results Using the full 5-variable CDST, we observed a linear trend of significantly lower rates of ED visits, hospitalisation, surgery, and healthcare-related costs with increasing probability of response (Table). These results were consistent when using the modified 3 variable CDST in the Optum patient dataset where we observed a 3-fold higher rate of per patient healthcare costs in the low probability of response group compared with the high probability of response group ($6535 vs. $1900, p = 0.016). In the Truven patient dataset, the modified 3 variable CDST was also associated with a significantly lower rate of hospitalisation, surgery, and healthcare costs in the high probability of response group (Table). The majority of cost differences between high and low response groups was driven by costs related to hospitalisation and surgery. Conclusion A simple CDST can identify CD patients treated with VDZ who present a higher risk for healthcare resource utilisation, especially for hospitalisation and surgery. This tool could be integrated into population health monitoring algorithms using real-world data and offer flexibility on requirements of lab data.

Inferring proxy response in household travel surveys with unknown completer using a group-based choice model

A proxy response is often accepted for household travel surveys to reduce the survey cost and increase the sample size, but proxy-response biases may be introduced into the sample data. To investigate and correct the bias, completer information for the survey is important, but such information is not always available in practice. This study proposes a novel model that can be applicable in situations where completer information is unavailable. The method introduces group-decision modeling in analyzing the response choices of the household travel survey, where the survey response is considered to be a task allocation among household members. The proposed model can infer the probability of proxy response and the proxy-response bias of trip-related records without completer information. The potential of the proposed model was confirmed by application to a household travel survey in Japan. The inferred probability of the proxy response and the inferred bias without completer data demonstrated surprisingly similar results to the existing study with actual proxy-response data. Specifically, the model inferred a high probability of proxy response in young adults and a low proxy probability in middle-aged females, and the model inferred the proxy-response bias that female proxy respondents in the middle-aged group report lower trip rates than self-respondents. This method will be valuable not only in travel surveys, but also in the general research and practice of social surveys.

688 Probability of Vedolizumab Response as Defined by Clinical Decision Support Tool Is Associated With Lower Risk of Serious Infection in Patients With Inflammatory Bowel Disease

INTRODUCTION: Disease activity is an independent predictor of infection in patients receiving biologics; non-response to a therapy might therefore present a higher risk of serious infection due to persistence of disease activity. We hypothesized that a clinical decision support tool (CDST) predicting lower treatment response may be predictive of a higher risk of infection. METHODS: Two validated CDSTs predicting vedolizumab (VDZ) response in ulcerative colitis (UC) and Crohn's disease (CD) were used on GEMINI phase 3 clinical trial data. After stratification by baseline variables into low, intermediate, or high probability of response to VDZ, time-to-event with Cox proportional hazard models was used to compare the risk of infection across groups and to identify independent predictors of infections among subgroups. RESULTS: 618 UC and 1023 CD patients were included. Those categorized as having low-intermediate probability of response (n = 479 UC, n = 814 CD) to VDZ were more likely to develop infectious complications while on therapy than those categorized as having high probability (n = 139 UC, n = 209 CD) response to VDZ (UC: hazard ratio [HR] 1.383, 95% confidence interval [CI] 1.024−1.868; CD: HR 1.458, 95% CI 1.124−1.893). Serious infections were observed in 1% of UC and 3% of CD patients in the high probability of response groups vs 2% of UC and 5% of CD patients in the low-intermediate groups. Among the low-intermediate probability of response UC group, independent predictors of developing infection were: baseline extraintestinal manifestations (no vs yes; HR 0.755, 95% CI 0.569−1.001); previous tumor necrosis factor antagonist exposure (no vs yes; HR 0.671, 95% CI 0.497−0.906); and baseline fecal calprotectin (log transformed; HR 1.135, 95% CI 1.016−1.268). Among the low-intermediate probability of response CD group, an independent predictor of developing infection was exposure to opioids during treatment (yes vs no; HR 1.829, 95% CI 1.469−2.277). CONCLUSION: This analysis confirms a pattern of inverse correlation between CDST-predicted efficacy and risk of infection. Data are consistent with the VDZ safety profile and suggest that infectious events seen were related to persistence of disease activity as opposed to drug-related mechanisms.

Relationship between protein biomarkers of chemotherapy response and microsatellite status, tumor mutational burden and PD-L1 expression in cancer patients.

Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti‐PD‐1/PD‐L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Data were extracted from a clinical‐grade testing database (Caris Life Sciences; February 2015 through November 2017): immunotherapy response markers (microsatellite instability‐high [MSI‐H], tumor mutational burden‐high [TMB‐H], and PD‐L1 protein expression) and protein chemotherapy response markers (excision repair complementation group 1 [ERCC1], topoisomerase 1 [TOPO1], topoisomerase 2 [TOP2A], thymidylate synthase [TS], tubulin beta 3 [TUBB3], ribonucleotide reductase regulatory subunit M1 [RRM1] and O‐6‐methyl guanine DNA methyltransferase [MGMT]). Relationships were determined by the Mantel‐Haenszel chi‐squared test or Fischer's exact tests. Overall, 28,034 patients representing a total of 40 tumor types were assessed. MSI‐H was found in 3.3% of patients (73% were also TMB‐H), TMB‐H, 8.4% (28.3% were also MSI‐H) and PD‐L1 expression in 11.0% of patients (5.1% were also MSI‐H; 16.4% were also TMB‐H). Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin or etoposide (TOP2A positivity) have a higher probability of response, whereas combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI‐H but not TMB‐H or PD‐L1‐expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD‐L1 is frequently coexpressed, but MSI‐H and TMB‐H are not associated. Protein markers of potential chemotherapy response along with next‐generation sequencing for immunotherapy response markers can help support rational combinations as part of an individualized, precision oncology approach.

P1237Left ventricular myocardial work characteristics and CRT response in patients with LBBB according to Strauss criteria and ESC 2013 definition

Abstract Background The impact of left bundle branch block (LBBB) on left ventricular (LV) myocardial work may vary according to the specific definition of a LBBB. Quantification of the interplay between LV myocardial work and the underlying electrical dyssynchrony may improve our understanding of cardiac resynchronization therapy (CRT) response. Objective To evaluate the impact of LBBB, defined according to Strauss and ESC 2013 ECG criteria, as well as non-LBBB morphologies on different LV myocardial work indices and response to CRT. Methods LBBB was defined according to the Strauss criteria and ESC 2013 guidelines on heart failure. LV myocardial constructive and wasted work (CW and WW) were derived from pressure-strain loop analysis integrating valvular opening and closing times, speckle tracking strain echocardiography and noninvasive blood pressure measurement. LV myocardial work efficiency (WE) was calculated from the ratio of constructive work, divided by the sum of constructive and wasted work. CRT response was defined as a decrease in LV end-diastolic volume (EDV) ≥15% at 6 months' follow-up. Results Patients were divided into 3 groups: 1) LBBB according to Strauss criteria (group 1, n=109, age 64±10 years), 2) LBBB according to ESC 2013 criteria (group 2, n=22, age 64±10 years) and 3) non-LBBB (group 3, n=44, age 69±10 years). Patients from group 1 were 4.2 times more likely to respond to CRT than patients from group 3 (odds ratio [OR] 4.182; 95% confidence interval [CI], 1.999–8.750; p&lt;0.001), whereas CRT response between groups 2 and 3 did not differ significantly (OR 1.100; 95% CI 0.387–3.124; p=0.859). Patients in group 1, were characterized by significantly lower WE, compared to groups 2 and 3 (67.6±9.9 mmHg% vs. 72.7±9.7 mmHg% and 75.4±9.6 mmHg%, respectively; p&lt;0.001) as well as higher WW (313.2±144.9 mmHg% vs. 215.1±102.5 mmHg% and 229.0±113.5 mmHg%, respectively; p&lt;0.001). There was no significant difference in CW between any of the groups (811.6±353.4 mmHg% vs. 798.6±440.6 mmHg% and 893.6±420.2 mmHg% respectively for groups 1, 2 and 3; p=0.447). Conclusion Patients with a LBBB according to Strauss criteria had a higher probability of response to CRT, compared to those with a LBBB defined by ESC 2013 guidelines criteria or with non-LBBB morphology. This is reflected in a greater amount of wasted work and more impaired LV myocardial work efficiency at baseline in patients with LBBB satisfying Strauss criteria, compared to the other two groups, representing the substrate for CRT. Acknowledgement/Funding Study was supported by ESC Research grant 2018

Stereotactic Radiation Therapy in Colorectal Cancer Brain Metastasis: An International, Multicentric Cohort

Colorectal cancer (CRC) is the third most common cancer in western countries, but brain metastases only occur in 1% of CRC patients. Overall survival in CRC patients rises as new systemic drugs became available. Thus the incidence of brain metastases in CRC patients will likely increase. We conducted a multicentric analysis to evaluate and compare the outcomes of stereotactic radiosurgery (SRS) and hypofractionated stereotactic radiotherapy (HFSRT) in CRC brain metastasis management. On behalf of the association of French-speaking neuro-oncologist (ANOCEF), we retrospectively collected individual data of patients treated with SRS or HFSRT for CRC brain metastases in 6 hospitals in France and Germany. The primary endpoint of the study was the radiological response rate defines as a complete response, partial response, or stability of the metastasis according to RANO BM criteria. The median follow-up from initial treatment was 31 months. The median response rate for metastasis treated was 65.9% (CI 95% [51.9% – 79.9%]) and was positively influenced by SRS whereas multiple brain metastases were related to poorest response rates as reported in the table below.Abstract 2188; Table 1ORSD2.5%97.5%p(OR<1)p(OR>1)Disease controlled0.730.510.172.050.790.21Multiple brain metastases0.720.520.162.050.800.20PTV volume (mL)0.990.030.941.040.700.30SRS3.274.120.3613.500.210.79 Open table in a new tab The median overall survival (OS) from initial treatment was ten months (CI 95% [5 – 22]). OS was negatively influenced by extra-cranial metastases, male gender, whereas it influenced positively by brain progression-free survival (BPFS). We report the results of one of the largest cohort of CRC brain metastasis treated with stereotactic radiotherapy. Our analysis suggests that age is associated with a higher response probability while the control of the disease is associated with a lower response probability. However, patients with a controlled disease are more likely to live longer and thus experience a progression of the treated metastasis. Finally, SRS seems to be associated with a higher response probability.

Optimizing venetoclax dose in combination with low intensive therapies in elderly patients with newly diagnosed acute myeloid leukemia: An exposure-response analysis.

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

Abstract 4928: Relationship between protein biomarkers of potential chemotherapy response and microsatellite status, tumor mutational burden, and PD-L1 expression in patients with cancer

Abstract Introduction: Chemotherapy and checkpoint inhibitor immunotherapies are increasingly used in combinations. We determined associations between the presence of anti-PD-1/PD-L1 therapeutic biomarkers and protein markers of potential chemotherapy response. Methods: Data was extracted from a clinical-grade testing database (Caris Life Sciences; Feb 2015 - Nov2017): immunotherapy response markers (microsatellite instability high (MSI-H) and tumor mutation burden-high (TMB-H) (by next generation sequencing (NGS)) and PD-L1 protein expression (immunohistochemistry); and protein chemotherapy response markers (ERCC1, TOPO1, TOP2A, TS, TUBB3, RRM1, and MGMT; immunohistochemistry). Relationships were determined by the Mantel-Haenszel chi-squared test or Fischer’s exact tests. Results: Overall, 28,034 patients (40 tumor types) were assessed. MSI-H was found in 3.3% of patients, TMB-H, 8.4%, and PD-L1 expression in 11.0% of patients. Based on concurrent biomarker expression, combinations of immunotherapy with platinum (ERCC1 negativity) or with doxorubicin, epirubicin, or etoposide (TOP2A positivity), have a higher probability of response while combinations with irinotecan or topotecan (TOPO1 positivity), with gemcitabine (RRM1 negativity), and fluorouracil, pemetrexed, or capecitabine (TS negativity) may be of less benefit. The potential for immunotherapy and taxane (TUBB3 negativity) combinations is present for MSI-H but not TMB-H or PD-L1-expressing tumors; for temozolomide and dacarbazine (MGMT negative), PD-L1 is frequently co-expressed, but MSI-H and TMB-H are not associated. Conclusion: Protein markers of potential chemotherapy response along with NGS for immunotherapy response markers can help support rational combinations as part of a precision oncology approach. Citation Format: Mina Nikanjam, David Arguello, Zoran Gatalica, Donald A. Barkauskas, Razelle Kurzrock. Relationship between protein biomarkers of potential chemotherapy response and microsatellite status, tumor mutational burden, and PD-L1 expression in patients with cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4928.